This project will investigate patterns of genetic variation in environmentally responsive genes identified by the NIEHS Environmental Genome Project. New theoretical and computational tools will be used to study the effects of population history and natural selection on environmentally sensitive genes in two study populations, the NIH DNA polymorphism discovery resource and a previously investigated sample of populations from Africa, Asia and Europe. Information about the effects of natural selection and population history in environmentally responsive genes will be useful in understanding their biology. A preliminary study in one gene (CYP1A2) shows that natural selection is an important consideration in the study of environmentally responsive genes, and may be a useful method for identifying functionally important genetic variants. Results of the project will lead to a better understanding of the underlying significance of variability in environmentally responsive genes, and into the origins of genetic diversity in general. [unreadable] [unreadable]